# NOX2 drives microglia-dependent neurodegeneration after traumatic brain injury

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $398,316

## Abstract

Project Summary: Traumatic brain injury (TBI) triggers delayed molecular secondary injury cascades, including
chronic neuroinflammation, that contribute to progressive tissue loss and neurological impairments, including
cognitive deficits. Chronic neuroinflammation with sustained microglial activation occurs following severe TBI
and is believed to contribute to subsequent neurodegeneration and neurological impairments. Thus, targeting
microglial activation may offer novel therapeutic targets for TBI patients. Our previous studies have probed the
development of dysfunctional microglia after TBI and shown that: 1) pro-inflammatory microglia are chronically
activated up to one year following experimental TBI, contributing to neurodegeneration and cognitive decline; 2)
NADPH oxidase (NOX2) plays a critical role for chronic microglial-mediated neurotoxicity; 3) temporary depletion
of brain microglia using a CSF1R inhibitor (PLX5622) causes microglial reprograming and phenotypic shift from
a chronic pro-inflammatory profile to more restorative phenotypes that express reduced inflammatory markers,
including NOX2 , and attenuate long-term motor and cognitive deficits. In the present proposal, we aim to utilize
the groundbreaking single-cell RNA-seq analyses to investigate the unique microglial subsets present following
specific targeted deletion of NOX2. Furthermore, we will investigate the transcriptional signatures of the
microglial subsets that modulate neurorestorative properties in the chronically injured brain. Importantly, this
proposal will investigate the role of NOX2 in non-microglia macrophage-like cells, including border-associated
macrophages (BAMs) and circulating monocytes, in mediating neuroinflammatory responses and neurological
decline, following TBI. Specific aims include: 1) To elucidate the mechanisms of repopulation-induced microglial
reprograming associated with attenuated pro-inflammatory, neurotoxic phenotypes after TBI; 2) To determine
the role of microglial NOX2 in neuroinflammation/neurodegeneration after TBI; 3) To address the role of BAM
NOX2 in in neuroinflammation/neurodegeneration after TBI; and 4) To evaluate the role of circulating monocytes
NOX2 in neuroinflammation/neurodegeneration after TBI. Understanding the molecular mechanisms that drive
microglia and non-microglia macrophage-like cells to polarize towards a neurorestorative state will be crucial to
unlock the endogenous potential of microglia/macrophages to promote repair during the chronic phase of
recovery after TBI.

## Key facts

- **NIH application ID:** 10536273
- **Project number:** 1R01NS129094-01
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** REBECCA HENRY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $398,316
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536273

## Citation

> US National Institutes of Health, RePORTER application 10536273, NOX2 drives microglia-dependent neurodegeneration after traumatic brain injury (1R01NS129094-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10536273. Licensed CC0.

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